PROJECT SUMMARY Major depressive disorder (MDD) is associated with high rates of disability, as well as suicidal ideation and behavior. Current treatments for MDD have significant limitations in efficacy and side effect burden, while FDA- approved devices for MDD are burdensome and only suitable for severely ill subjects. There is a critical need for device-based treatments in MDD that are efficacious, well-tolerated and easy to use. Transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light penetrates robustly into the cerebral cortex and This project focuses on the adjunctive use of the transcranial photobiomodulation (t-PBM) with near- infrared (NIR) light for the treatment of MDD. t-PBM with near-infrared (NIR) light penetrates robustly into the cerebral cortex, stimulating the mitochondrial respiratory chain, and also significantly increases cerebral blood flow (CBF). In the R61 phase, we will conduct target engagement studies to demonstrate dose-dependent effects of t-PBM on the prefrontal cortex (PFC) CBF, using the increase in fMRI blood-oxygenation-level dependent (BOLD) signal levels as our Go/No-go target engagement biomarker. In the R33 phase, we will conduct a randomized clinical trial of t-PBM vs. sham for in MDD, to establish the target engagement and evaluate the association between changes in the biomarker (BOLD signal) and changes in clinical symptoms, while also collecting important information on antidepressant effects, safety and tolerability. The study will be done in parallel at the New York University/ Nathan Kline Institute and at Massachusetts General Hospital. The importance of this study is threefold: (1) it targets MDD, a leading cause of disability wordwide, which lacks adequate treatments, (2) it evaluates t-PBM, which has a well-established safety profile and has the potential to be safe in at-home administration, and (3) uses fMRI BOLD changes as a target engagement biomarker. If effects are confirmed, the present study will both support short-term clinical development of an easy to scale device for the treatment of MDD, while also validating a biomarker for the development of future, novel modulation strategies.